Predictive Structure-based Guidelines for Identifying Optimal PEGylation Sites within Proteins

用于识别蛋白质内最佳聚乙二醇化位点的基于预测结构的指南

• 批准号: 8958215
• 负责人: Joshua L Price
• 金额: $ 34.56万
• 依托单位: BRIGHAM YOUNG UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8958215
• 关键词: Antibodies; Biological; Chickens; Development; Drug Kinetics; Figs - dietary; Goals; Granulocyte Colony-Stimulating Factor; Guidelines; Health; Human; Immunoglobulin G; Interferons; Lead; Learning; Length; Location; Maleimides; Modeling; Molecular; Peptides; Pharmaceutical Preparations; Pin1 protein; Polyethylene Glycols; Polymers; Positioning Attribute; Property; Proteins; Proteolysis; Relative (related person); SH3 Domains; Side; Site; Site-Directed Mutagenesis; Solvents; Structure; Techniques; Therapeutic; Triad Acrylic Resin; Work; base; molecular dynamics; protein folding; protein misfolding; public health relevance; therapeutic protein; tool

 DESCRIPTION (provided by applicant): Our goal is to develop structure-based tools for identifying optimal PEGylation sites within peptides/proteins and to use these tools to enhance peptide/protein pharmacokinetic properties. Our central hypothesis is that optimal PEGylation sites should be characterized by the ability of the attached PEG to enhance peptide/protein conformational stability. Our rationale for this hypothesis is that unstable, unfolded or misfolded proteins tend to be non-functional and have more pharmacokinetic problems than folded proteins (i.e., are more aggregation-prone, more susceptible to proteolysis, and more readily recognized by antibodies). Therefore increases in protein conformational stability should also enhance protein pharmacokinetic properties However, current PEGylation efforts lack predictive tools for increasing protein stability; instead, a trial-and-error approach prevails, which frequenly results in diminished biological activity relative to the non-PEGylated protein. Using our growing molecular-level understanding of PEG-based protein stabilization, we will develop predictive structure-based tools for generating PEGylated peptides/proteins with enhanced pharmacokinetic properties and undiminished function, thereby accelerating the development of better PEGylated protein drugs.

 描述(由申请人提供)：我们的目标是开发基于结构的工具，以确定多肽/蛋白质中的最佳聚乙二醇化位点，并使用这些工具来增强多肽/蛋白质的药代动力学特性。我们的中心假设是，最佳的聚乙二醇化位点的特征应该是结合的聚乙二醇能增强多肽/蛋白质构象的稳定性。我们对这一假设的理由是，不稳定、展开或错误折叠 蛋白质往往是无功能的，比折叠蛋白质有更多的药代动力学问题(即，更容易聚集，更容易蛋白质分解，更容易被抗体识别)。因此，蛋白质构象稳定性的提高也应该增强蛋白质的药代动力学性质。然而，目前的聚乙二醇化努力缺乏提高蛋白质稳定性的预测工具；相反，一种反复试验的方法盛行，这经常导致相对于非聚乙二醇化蛋白质的生物活性降低。利用我们对基于聚乙二醇基的蛋白质稳定性的日益深入的分子水平的了解，我们将开发基于预测结构的工具，以产生具有增强的药代动力学特性和不降低功能的聚乙二醇化多肽/蛋白质，从而加速更好的聚乙二醇化蛋白质药物的开发。